3-Thia-4-arylquinolin-2-one derivatives as smooth muscle relaxants

ABSTRACT

This invention describes compounds of Formula (I) which are modulators of potassium channels and are useful for treating conditions affected by abnormal potassium channel activity including erectile dysfunction and irritable bowel syndrome.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/511,056 filed Oct. 14, 2003.

BACKGROUND OF THE INVENTION

Potassium channels are transmembrane proteins which are ubiquitouslyexpressed in mammalian cells and represent one of the largest and themost diverse group of ion channels from a molecular perspective.Potassium channels play a key role in regulation of cell membranepotential and modulation of cell excitability. Potassium channels arelargely regulated by voltage, cell metabolism, calcium and receptormediated processes. [Cook, N. S., Trends in Pharmacol. Sciences 1988, 9,21; and Quast, U., et al., Trends in Pharmacol. Sciences 1989, 10, 431].Calcium-activated potassium (K_(Ca)) channels are a diverse group of ionchannels that share a dependence on intracellular calcium ions foractivity. The activity of K_(ca) channels is regulated by intracellular[Ca²⁺], membrane potential and phosphorylation. On the basis of theirsingle-channel conductances in symmetrical K⁺ solutions, K_(Ca) channelsare divided into three subclasses: large conductance (BK or Maxi-K) arethose having a conductance of greater than about 150 picosemens (pS);intermediate conductance are those having a conductance of about 50–150pS; and small conductance are those having a conductance of less thanabout 50 pS. Large-conductance calcium-activated potassium channels arepresent in many excitable cells including neurons, cardiac cells andvarious types of smooth muscle cells. [Singer, J. et al., PflugersArchiv. 1987, 408, 98; Baro, I., et al., Pflugers Archiv. 1989, 414(Suppl. 1), S168; and Ahmed, F. et al., Br. J. Pharmacol. 1984, 83,227].

Potassium ions play a dominant role in controlling the resting membranepotential in most excitable cells and maintain the transmembrane voltagenear the K⁺ equilibrium potential (E_(k)) of about −90 millivolts (mV).It has been shown that opening of potassium channels shift the cellmembrane potential towards the E_(k), resulting in hyperpolarization ofthe cell. [Cook, N. S., Trends in Pharmacol. Sciences 1988, 9, 21].Hyperpolarized cells show a reduced response to potentially damagingdepolarizing stimuli. Those BK channels which are regulated by bothvoltage and intracellular Ca²⁺ act to limit depolarization and calciumentry and may be particularly effective in blocking damaging stimuli.Therefore cell hyperpolarization via opening of BK channels may resultin protection of neuronal cells, as well as other types of cells, e.g.,cardiac cells. [Xu, W., Liu, Y., Wang, S., McDonald, T., Van Eyk, J. E.,Sidor, A., and O'Rourke, B. Cytoprotective Role of Ca²⁺-activated K⁺Channels in the Cardiac Inner Mitochondrial Membrane. Science 2002, 298,1029–1033].

BK channels have been shown to be one of two physiologically relevantpotassium channels in relaxing human smooth muscle, including bothintestinal and penile smooth muscle. Evidence that relaxation of smoothmuscle is beneficial to irritible bowel syndrome and erectiledysfunction has been reported. See the following references: Christ, G.J. Drug News Perspect. 2000, 13, 28–36; Poynard T. et al. AlimentaryPharmacology and Therapeutics 2001, 15, 355–361; and Argentieri, T. M.U.S. patent application Ser. No. 2002/0183395.

A variety of synthetic and naturally occurring compounds with BK openingactivity have been reported. 4-Aryl-3-hydroxyquinolin-2-one derivativesare disclosed in U.S. Pat. No. 5,892,045, issued Apr. 6, 1999; U.S. Pat.No. 5,922,735, issued Jul. 13, 1999; U.S. Pat. No. 6,353,119, issuedMar. 5, 2002. 4-Arylquinolin-2-one derivatives are disclosed in U.S.Pat. No. 6,184,231, published Feb. 6, 2001 and U.S. Pat. No. 5,972,961,published Oct. 26, 1999. See also Hewawasam, P. et. al. J. Med. Chem. 462819–2822 (2003). Other quinolinones are disclosed in U.S. Pat. No.6,538,022; Japanese Pat. No. 2002371078; and PCT patent application WO2002026713.

Despite advances in the art, further advances are needed for compoundscapable of modulating potassium channels, in particular,large-conductance calcium-activated potassium channels. Such compoundswould be useful in treating conditions arising from dysfunction ofcellular membrane polarization and conductance.

SUMMARY OF THE INVENTION

This invention describes 3-thia-4-arylquinolin-2-one compounds havingthe general formula I or pharmaceutically acceptable salts or solvatesthereof,

wherein R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and m are as defined below.

The present invention also provides pharmaceutical compositionscomprising the atropisomers of 3-thia-4-arylquinolin-2-one derivativesand methods for the treatment of conditions sensitive to potassiumchannel opening activity such as, for example, ischemia, stroke,convulsions, epilepsy, asthma, irritable bowel syndrome, migraine,traumatic brain injury, spinal cord injury, sexual dysfunction andurinary incontinence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes novel 3-thia-4-arylquinolin-2-onecompounds and related derivatives of Formula (I) or pharmaceuticallyacceptable salts or solvates thereof

wherein:

-   R and R¹ are independently hydrogen or methyl;-   R², R³, and R⁴ are independently hydrogen, halogen, cyano, nitro, or    trifluoromethyl, provided R², R³, and R⁴ are not all hydrogen;-   R⁵ is bromo, chloro, or nitro;-   R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₃₋₇    cycloalkyl, —CH₂C₃₋₇ cycloalkyl, —(CH₂)₁₋₃OH, —(CH₂)₂₋₃NR⁸R⁹,    —(CH₂)₁₋₃CN, or —(CH₂)₁₋₃Ar, where Ar is selected from the group    consisting of phenyl, naphthyl, furanyl, thienyl, and pyridyl, and    Ar is unsubstituted or substituted with 1–2 methoxy substituents; or-   NR⁶R⁷ taken together form    or-   NR⁶R⁷ taken together are selected from the group consisting of-   R⁸ and R⁹ are independently hydrogen or C₁₋₆alkyl;-   R¹⁰ is a bond, O, S, NR¹¹, or CHR¹²;-   R¹¹ is hydrogen, C₁₋₆ alkyl, CHO, C(O)Me, —(CH₂)₂₋₃OH,    —CH₂CH₂OCH₂CH₂OH, —C(O)furanyl, or —CH₂CH═CHPh;-   R¹² is hydrogen, hydroxy, C₁₋₆ alkyl, —CH₂Ph, —C(O)OR⁸, —(CH₂)NR⁸R⁹,    or 1-piperidinyl; and-   m is 0, 1, 2, or 3.

The present invention also provides a method for the treatment oralleviation of disorders associated with BK channels, such as ischemia,stroke, convulsions, epilepsy, asthma, migraine, traumatic brain injury,spinal cord injury, sexual dysfunction, urinary incontinence andespecially male erectile dysfunction and irritable bowel syndrome whichcomprises administering together with a conventional adjuvant, carrieror dilutent a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

The term “atropisomer” refers to a stereoisomer resulting fromrestricted rotation about a single bond where the rotation barrier ishigh enough to permit isolation of the isomeric species.

The invention encompasses all stereoisomers and tautomers, includingatropisomers. Examples of atropisomers and tautomers are shown below.

The terms “racemic mixture” and “racemate” refer to an equimolar ornearly equimolar mixture of two enantiomeric species. In addition, asused herein, the terms “racemic mixture” and “racemate” are intended toinclude equimolar mixtures of the two atropisomers.

The term “pharmaceutically acceptable salt” is intended to includenontoxic salts synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th ed., Mack PublishingCompany, Easton, Pa., 1990, p. 1445. Suitable inorganic bases such asalkali and alkaline earth metal bases include metallic cations such assodium, potassium, magnesium, calcium and the like. The compounds of thepresent invention are useful in the form of the free base or acid or inthe form of a pharmaceutically acceptable salt thereof. All forms arewithin the scope of the invention.

The term “halogen” as used herein and in the claims is intended toinclude fluorine, bromine, chlorine and iodine while the term “halide”is intended to include fluoride, bromide, chloride and iodide anion.

The term “therapeutically effective amount” means the total amount ofeach active component that is sufficient to show a meaningful patientbenefit, i.e., amelioration of acute conditions characterized by openersof large conductance calcium-activated K⁺ channels or increase in therate of such conditions. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously.

The term “compounds of the invention”, and equivalent expressions, aremeant to embrace compounds of Formula I and include prodrugs,pharmaceutically acceptable salts, and solvates, e.g. hydrates.Similarly, reference to intermediates, whether or not they themselvesare claimed, is meant to embrace their salts, and solvates, where thecontext so permits.

The term “derivative” means a chemically modified compound wherein themodification is considered routine by the ordinary skilled chemist, suchas an ester or an amide of an acid, protecting groups, such as a benzylgroup for an alcohol or thiol, and tert-butoxycarbonyl group for anamine.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules. This physical associationincludes hydrogen bonding. In certain instances the solvate will becapable of isolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolable solvates. Exemplarysolvates include hydrates, ethanolates, methanolates, and the like.

The term “patient” includes both human and other mammals.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutical carrier, i.e., adjuvant, excipient or vehicle, such asdiluents, preserving agents, fillers, flow regulating agents,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavoring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispensing agents, depending on the nature of the mode of administrationand dosage forms. Ingredients listed in Remington's PharmaceuticalSciences, 18^(th) ed., Mack Publishing Company, Easton, Pa. (1999) forexample, may be used.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable risk/benefit ratio.

The term “pharmaceutically acceptable prodrugs” as used herein meansthose prodrugs of the compounds useful according to the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable risk/benefit ratio, and effective fortheir intended use, as well as zwitterionic forms, where possible, ofthe compounds of the invention.

The term “prodrugs”, as the term is used herein, are intended to includeany covalently bonded carriers which release an active parent drug ofthe present invention in vivo when such prodrug is administered to apatient. Since prodrugs are known to enhance numerous desirablequalities of pharmaceuticals (i.e., solubility, bioavailability,manufacturing, etc.) the compounds of the present invention may bedelivered in prodrug form. Thus, the skilled artisan will appreciatethat the present invention encompasses prodrugs of the presently claimedcompounds, methods of delivering the same, and compositions containingthe same. Prodrugs of the present invention are prepared by modifyingfunctional groups present in the compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, toform the parent compound. The transformation in vivo may be, forexample, as the result of some metabolic process, such as chemical orenzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, orreduction or oxidation of a susceptible functionality. Prodrugs includecompounds of the present invention wherein a hydroxy, amino, orsulfhydryl group is bonded to any group that, when the prodrug of thepresent invention is administered to a patient, it cleaves to form afree hydroxyl, free amino, or free sulfydryl group, respectively.Functional groups which may be rapidly transformed, by metaboliccleavage, in vivo form a class of groups reactive with the carboxylgroup of the compounds of this invention. They include, but are notlimited to such groups as alkanoyl (such as acetyl, propionyl, butyryl,and the like), unsubstituted and substituted aroyl (such as benzoyl andsubstituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl),trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formedwith dicarboxylic acids (such as succinyl), and the like. Because of theease with which the metabolically cleavable groups of the compoundsuseful according to this invention are cleaved in vivo, the compoundsbearing such groups can act as prodrugs. The compounds bearing themetabolically cleavable groups have the advantage that they may exhibitimproved bioavailability as a result of enhanced solubility and/or rateof absorption conferred upon the parent compound by virtue of thepresence of the metabolically cleavable group. A thorough discussion ofprodrugs is provided in the following: Design of Prodrugs, H. Bundgaard,ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed.,Academic Press, 42, p. 309–396, 1985; A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Designand Applications of Prodrugs” p. 113–191, 1991; Advanced Drug DeliveryReviews, H. Bundgard, 8, p. 1–38, 1992; Journal of PharmaceuticalSciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p.692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V.Stella, Vol. 14 of the A.C.S. Symposium Series, and BioreversibleCarriers in Drug Design, Edward B. Roche, ed., American PharmaceuticalAssociation and Pergamon Press, 1987.

One aspect of the invention are compounds of Formula I where R ishydrogen.

Another aspect of the invention are compounds of Formula I where R¹ ishydrogen.

Another aspect of the invention are compounds of Formula I where R¹ ishydrogen, R³ is trifluoromethyl, and R⁴ is hydrogen.

Another aspect of the invention are compounds of Formula I where R¹ ischloro.

Another aspect of the invention are compounds of Formula I where m is 3.

Some compounds of the invention include

-   (1)    4-(5-Chloro-2-hydroxy-phenyl)-3-(4-morpholin-4-yl-2-oxo-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one;-   (2)    4-(5-Chloro-2-hydroxy-phenyl)-3-(2-oxo-4-pyrrolidin-1-yl-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one;-   (3)    4-(5-Chloro-2-hydroxy-phenyl)-3-[4-(4-methyl-piperazin-1-yl)-2-oxo-butylsulfanyl]-6-trifluoromethyl-1H-quinolin-2-one;-   (4)    4-(5-Chloro-2-methoxy-phenyl)-3-(4-morpholin-4-yl-2-oxo-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one;-   (5)    4-(5-Chloro-2-hydroxy-phenyl)-3-[2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethylsulfanyl]-6-trifluoromethyl-1H-quinolin-2-one;-   (6)    4-(5-Chloro-2-methoxyphenyl)-3-[[4-(diethylamino)-2-oxobutyl]thio]-6(trifluoromethyl)-2(1H)-quinolinone;-   (7)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-4-(1-piperidinyl)butyl]thio]-6(trifluoromethyl)-2(1H)-quinolinone;-   (8)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-4-(4-thiomorpholinyl)butyl]thio]-6(trifluoromethyl)-2(1H)-quinolinone;-   (9)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(dihexylamino)-2-oxobutyl]thio]-6(trifluoromethyl)-2(1H)-quinolinone;-   (10)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(3-hydroxy-1-pyrrolidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (11)    1-[4-[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)    -3-quinolinyl]thio]-3-oxobutyl]-(2S)-2-pyrrolidinecarboxamide;-   (12)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(cyclohexylmethylamino)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (13)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[(cyclopropylmethyl)propylamino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (14)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-4-[(2-phenylethyl)(phenylmethyl)amino]butyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;-   (15)    1-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)    -3-quinolinyl]thio]-3-oxobutyl]-3-piperidinecarboxylic acid, ethyl    ester;-   (16) 4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(octahydro-1    (2H)-quinolinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (17)    4-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)    -3-quinolinyl]thio]-3-oxobutyl]-1-piperazinecarboxaldehyde;-   (18)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[(2-furanylmethyl)methylamino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (19)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(dipropylamino)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (20)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(2-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (21)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (22)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(5-ethyl-2-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (23)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[2-(2-hydroxyethyl)-1-piperidinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (24)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[3-(hydroxymethyl)-1-piperidinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (25)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[methyl(2-methylpropyl)amino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (26)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[methyl(2-phenylethyl)amino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (27)    1-Acetyl-4-[4-[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]piperazine;-   (28)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(3-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (29)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(4-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (30)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(4-hydroxy-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (31)    1-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-3-piperidinecarboxamide;-   (32)    3-[[4-(Butylethylamino)-2-oxobutyl]thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;-   (33)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[methyl(1-methyl-3-pyrrolidinyl)amino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (34)    1-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-4-piperidinecarboxylic    acid, ethyl ester;-   (35)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[[3-(dimethylamino)propyl]methylamino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;-   (36)    4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[2-(hydroxymethyl)-1-piperidinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (37)    3-[(4-[1,4′-Bipiperidin]-1′-yl-2-oxobutyl)thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;-   (38)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-morpholinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (39)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-(1-piperidinyl)pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (40)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-(4-thiomorpholinyl)pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (41)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-methyl-1-piperazinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (42)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(3-hydroxy-1-pyrrolidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (43)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(cyclohexylmethylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (44)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[(cyclopropylmethyl)propylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (45)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-[(2-phenylethyl)(phenylmethyl)amino]pentyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;-   (46)    1-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-    3-quinolinyl]thio]-4-oxopentyl]-3-piperidinecarboxylic acid, ethyl    ester;-   (47) 4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(octahydro-1    (2H)-quinolinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (48)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[2-(hydroxymethyl)-1-pyrrolidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (49)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-[4-(phenylmethyl)-1-piperidinyl]pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (50)    4-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)    -3-quinolinyl]thio]-4-oxopentyl]-1-piperazinecarboxaldehyde;-   (51)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[(2-furanylmethyl)methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (52)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(dipropylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (53)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[2-(dimethylamino)ethyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;-   (54)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[(2-hydroxy-2-phenylethyl)methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (55)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(2-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (56)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[4-(2-hydroxyethyl)-1-piperazinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (57)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(5-ethyl-2-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (58)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[2-(2-hydroxyethyl)-1-piperidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (59)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[3-(hydroxymethyl)-1-piperidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (60)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl(2-methylpropyl)amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (61)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl(2-phenylethyl)amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (62)    3-[[5-[Butyl(phenylmethyl)amino]-2-oxopentyl]thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;-   (63)    1-Acetyl-4-[5-[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]piperazine;-   (64)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-(1-pyrrolidinyl)pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (65)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(3-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (66)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (67)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-hydroxy-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (68)    4-(5-chloro-2-hydroxyphenyl)-3-[[5-[methyl(1-methyl-3-pyrrolidinyl)amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (69)    1-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-    3-quinolinyl]thio]-4-oxopentyl]-4-piperidinecarboxylic acid, ethyl    ester;-   (70)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[3-(dimethylamino)propyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (71)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[2-(hydroxymethyl)-1-piperidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (72)    3-[(5-[1,4′-Bipiperidin]-1′-yl-2-oxopentyl)thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;-   (73)    3-[[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)3-quinolinyl]thio]-4-oxopentyl]methylamino]propanenitrile;-   (74)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(cyclohexyl-2-propenylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (75)    3-[[5-[bis(Phenylmethyl)amino]-2-oxopentyl]thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;-   (76)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (77)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[2-(diethylamino)ethyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (78)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(di-2-propenylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (79)    1-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]-4-(2-furanylcarbonyl)piperazine;-   (80)    4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-[4-[(2E)-3-phenyl-2-propenyl]-1-piperazinyl]pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (81)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;-   (82)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (83)    4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl[1-(1-naphthalenyl)ethyl]amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;-   (84)    1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-methylpiperazine;-   (85)    4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]morpholine;-   (86)    1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]pyrrolidine;-   (87)    4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]thiomorpholine;-   (88)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N,N-diethylacetamide;-   (89)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N,N-bis(2-hydroxypropyl)acetamide;-   (90)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(diethylamino)ethyl]-N-methylacetamide;-   (91)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[3-(4-morpholinyl)propyl]acetamide;-   (92)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-(3-pyridinylmethyl)acetamide;-   (93)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(2-thienyl)ethyl]acetamide;-   (94)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(1-pyrrolidinyl)ethyl]acetamide;-   (95)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(4-pyridinyl)ethyl]acetamide;-   (96)    1-Acetyl-4-[[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]piperazine;-   (97)    4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazinecarboxaldehyde;-   (98)    2-[2-[4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazinyl]ethoxy]ethanol;-   (99)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-ethyl-N-(4-pyridinylmethyl)acetamide;-   (100)    1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]hexahydro-4-methyl-1H-1,4-diazepine;-   (101)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-(cyclopropylmethyl)-N-propylacetamide;-   (102)    4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazinecarboxylic    acid, ethyl ester;-   (103)    4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazineethanol;-   (104)    1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-piperidinecarboxylic    acid, ethyl ester;-   (105)    1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-piperidinecarboxamide;-   (106)    2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-(2-hydroxyethyl)-N-methylacetamide;-   (107)    4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazineacetic    acid, ethyl ester; and-   (108)    1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-oxo-3-piperidinecarboxylic    acid, ethyl ester;    and salts and solvates thereof.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms including hydrated forms suchas monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and thelike. The products may be true solvates, while in other cases, theproducts may merely retain adventitious solvent or be a mixture ofsolvate plus some adventitious solvent. It should be appreciated bythose skilled in the art that solvated forms are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Synthetic Methods

The compounds of Formula I may be prepared by various procedures such asthose illustrated herein in the examples and in the Reaction Schemesdescribed in the specific embodiments and variations thereof which wouldbe evident to those skilled in the art.

The following reaction schemes illustrate representative generalprocedures for the preparation of intermediates and methods for thepreparation of compounds of Formula I according to this invention. Itshould also be evident to those skilled in the art that appropriatesubstitution of both the materials and methods disclosed herein willproduce the examples illustrated below and those encompassed by thescope of this invention.

Reagents and conditions: (a) bromoacetyl bromide, pyridine, CH₂Cl₂, 0°C.

Reagents and conditions: (m) NaH, p-methoxybenzyl mercaptan, THF, V, 0°C. to r.t.; (n) Trifluoroacetic acid; (o) NaH, 2-methyl-2-propanethiol,THF, V, 0° C. to r.t. to reflux; (p) BBr3, CH2Cl2, −78° C. to r.t.

Reagents and conditions: (q) 1-bromo-4-methoxy-butan-2-one, K₂CO₃, EtOH(r) amine, K₂CO₃, ethanol, THF; (t) 1,5-dichloropentan-2-one, K₂CO₃,EtOH; (u) amine, THF

Reagents and conditions: (w) (i. BBr₃, CH₂Cl₂), ii. NaH, methylthioglycolate, THF, V, r.t.; (x) 10 N NaOH, THF; (y) amine, EDC,1,2-dichloroethane, THF.

Biological Methods

Openers of BK channels exert their cellular effects by increasing theopen probability of these channels [Gribkoff, V. K., et al.,Neuroscientist, 7:166–177 (2001); Gribkoff, V. K. et al., Adv.Pharmacol., 37:319–348 (1997); McKay, M. C., et al., J. Neurophysiol.,71: 1873–1882 (1994); and Olesen, S.-P., Exp. Opin. Invest. Drugs, 3:1181–1188 (1994)]. This increase in the opening of individual BKchannels collectively results in the hyperpolarization of cellmembranes, particularly in depolarized cells, produced by significantincreases in whole-cell BK-mediated conductance. Hyperpolarization, inturn, reduces the excitability of nerve and muscle cells, and decreasesthe open probability of voltage-dependent Ca²⁺ channels, effectivelylowering intracellular concentrations of this potentially harmfulcation. The effect on smooth muscle is that of relaxation.

Assay for BK Channel Openers

The ability of the compounds of the invention to open BK channels andincrease whole-cell outward (K⁺) BK-mediated currents was assessed undervoltage-clamp conditions by determining their ability to increase clonedmammalian (mSlo or hSlo) BK-mediated outward current heterologouslyexpressed in Xenopus oocytes [Butler, A., et al., Science 1993, 261,221–224; Dworetzky, S. I., et al., Mol. Brain Res. 1994, 27, 189–193;Gribkoff, V. K., et al., Mol. Pharmacol. 1996, 50, 206–217]. The two BKconstructs employed represent nearly structurally identical homologousproteins, and have proven to be pharmacologically indistinguishable inour tests. To isolate BK current from native (background, non-BK)current, the specific and potent BK channel-blocking toxin iberiotoxin(IBTX) [Galvez, A., et al., J. Biol. Chem. 1990, 265, 11083–11090] wasemployed at a supramaximal concentration, e.g., 50–100 nanomolar (“nM”).The relative contribution of BK channel-mediated current to totaloutward current was determined by subtraction of the current remainingin the presence of IBTX (non-BK current) from the current profilesobtained in all other experimental conditions (control, drug, and wash)[Gribkoff, V. K. et al., Mol. Pharmacol. 1996, 50, 206–217]. It wasdetermined that at the tested concentrations the compounds profiled didnot significantly effect non-BK native currents in the oocytes. Allcompounds were tested in 5–10 oocytes and are reported at the indicatedconcentration of 20 micromolar (“μM”) (or as otherwise indicated); theeffect of the selected compounds of the invention on BK current wasexpressed as the percent of control IBTX-sensitive current at a singletransmembrane voltage (+140 mV) and is listed in Table 1. Recordingswere accomplished using standard two-electrode voltage clamp techniques[Stuhmer, W., et al., Methods in Enzymology, 1992, 207, 319–339];voltage-clamp protocols consisted of 500–750 milliseconds (“ms”)duration step depolarizations, from a holding potential of −60 mV, to afinal voltage up to +140 mV in 20 mV steps. The experimental media(modified Barth's solution) consisted of millimolar (“mM”): NaCl (88),NaHCO₃ (2.4), KCl (1.0), HEPES (10), MgSO₄ (0.82), Ca(NO₃)₂ (0.33),CaCl₂ (0.41); pH 7.5.

Rat Small Intestine

The ability of the compounds of the invention to relax rat smallintestine tissue as a model for the treatment of irritable bowelsyndrome is described as follows. Male rats (Harlan, Sprague Dawley,250–350 g) were sacrificed by decapitation. A portion of small intestine(ileum) was removed and the attached connective tissues and intestinalcontents removed. The ileum was cut into segments of ≦1 cm in length.The segments were mounted longitudinally between fixed hooks in organbaths containing warm (37° C.) physiological salt solution (compositionin mM: NaCl 118.4, KCl 4.7, KH₂PO4 1.2, MgSO₄ 1.2, CaCl₂ 1.8, Glucose10.1, NaHCO₃ 25; gassed with 95% O₂/5% CO₂, pH 7.4). A stable tension of˜1.5 g was maintained in the tissue segments during the equilibrationperiod of 45 minutes. Changes in muscle tension were measured withisometric force transducers (Grass, FT-03C) and recorded usingAcqKnowledge data acquisition system (AcqKnowledge for MP100WS, BiopacSystems Inc., Goleta, Calif.). Compound or vehicle was added in thebaths for 30 minutes. “Zero” active force was established at the end ofthe experiment using nifedipine (20 μM). The effects of compounds orvehicle on force was determined by measuring the integral ofnifedipine-sensitive force (including resting tone and spontaneouscontractions) pre- and 30 min post-compound (or vehicle) addition.Results are expressed as the percentage inhibition of force. DMSOvehicle inhibited force (integral) by −0.6±3.0% (n=25). Results aresummarized in Table 1.

Rabbit Corpus Cavernosum

The ability of the compounds of the invention to relax rabbit corpuscavernosum tissue as a model for the treatment of erectile dysfunctionis described as follows. New Zealand white rabbits (3.4–3.7 kg) wereeuthanized by sodium pentobarbital (100 mg/kg) overdose. The penis fromeach animal was rapidly removed and immersed in a cold oxygenatedmodified Krebs Henseleit bicarbonate buffer. The penis' outer tunica wasremoved and the corpus cavernosum smooth muscle obtained and cut intostrips approximately 3–5 mm long. The strips were suspended in tissuebaths containing physiological salt solution (see above), and allowed toequilibrate for at least one hour under resting tension of 1.0 gram.Isometric force was measured as described above. Tissue strips werestimulated with the α-agonist phenylephrine (3 μM) and allowed to reacha steady level of force prior to the addition of test compounds. Theresults are expressed as the percentage inhibition ofphenylephrine-induced force as compared to vehicle control. Results aresummarized in Table 1.

TABLE 1 % Inhibition % Inhibition % MaxiK of force of force Ex.Structure opening* (RCC strips) (RSI strips) 2

335 30 3

550 5

286 34.5 58.5 7

199 29 21

241 30

235 35

178 63

284 65

271 66

213 68

226 72

298 84

422 14.4 98

205 17 9 103

151 22 22.5 105

203 67 62 107

281 19 46

The results of the above biological tests demonstrate that the compoundsof the invention are potent openers of large-conductancecalcium-activated K⁺ channels (BK or Maxi-K channels) and are effectiveat relaxing intestinal and penile smooth muscle.

Pharmaceutical Compositions and Methods of Use

The compounds of the present invention are useful for the treatment ofpatients for conditions arising from dysfunction of cellular membranepolarization and conductance and are indicated for the treatment ofischemia, stroke, convulsions, epilepsy, asthma, migraine, traumaticbrain injury, spinal cord injury, sexual dysfunction, urinaryincontinence and especially male erectile dysfunction and irritablebowel syndrome, as well as other disorders sensitive to BK channelactivity. Accordingly, in one aspect of the present invention, there isprovided a method of treatment or prevention of conditions responsive toopening of potassium channels in a patient in need thereof, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable salt,solvate or prodrug thereof. In another aspect, this invention provides amethod for the treatment of or protection from disorders which aremediated by opening of the large conductance calcium-activated K⁺channels in a patient in need thereof, which comprises administering tothe patient a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt, solvate or prodrug thereof.Preferably, the compounds of Formula I are useful in the treatment ofischemia, stroke, convulsions, asthma, irritable bowel syndrome,migraine, traumatic brain injury, urinary incontinence, irritable bowelsyndrome, and sexual dysfunction in both men (erectile dysfunction, forexample, due to diabetes mellitus, spinal cord injury, radicalprostatectomy, psychogenic etiology or any other cause) and women byimproving blood flow to the genitalia, especially the corpus cavernosum,and other disorders sensitive to BK channel activating activity.

In another aspect, this invention provides pharmaceutical compositionscomprising at least one compound of Formula I and a carrier.

The pharmaceutical compositions include suitable dosage forms for oral,parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, placed in a hard gelatincapsule in powder or pellet form, or in the form of a troche or lozenge.The solid carrier may contain conventional excipients such as bindingagents, fillers, tableting lubricants, disintegrants, wetting agents andthe like. The tablet may, if desired, be film coated by conventionaltechniques. If a liquid carrier is employed, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule, sterile vehicle forinjection, an aqueous or non-aqueous liquid suspension, or may be a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Liquid preparations may contain conventional additives such assuspending agents, emulsifying agents, wetting agents, non-aqueousvehicle (including edible oils), preservatives, as well as flavoringand/or coloring agents. For parenteral administration, a vehiclenormally will comprise sterile water, at least in large part, althoughsaline solutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Particularlyuseful is the administration of a compound of Formula I directly inparenteral formulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula I according to the invention.

The dosage of the compounds of Formula I to achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of potassiumchannel activating activity desired and the potency of the particularcompound being utilized for the particular disorder of diseaseconcerned. It is also contemplated that the treatment and dosage of theparticular compound may be administered in unit dosage form and that theunit dosage form would be adjusted accordingly by one skilled in the artto reflect the relative level of activity. The decision as to theparticular dosage to be employed (and the number of times to beadministered per day) is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition as described herein is an amount of active ingredientfrom about 0.01 micrograms per kilogram (μg/kg) to 50 milligrams perkilogram (mg/kg) body weight and preferrably, from about 0.1 μg/kg to 5mg/kg body weight for oral administration. For parenteraladministration, the dose may be in the range of 0.1 μg/kg to 1 mg/kgbody weight for intravenous administration. The active ingredient willpreferably be administered in equal doses from one to four times a day.However, usually a small dosage is administered, and the dosage isgradually increased until the optimal dosage for the host undertreatment is determined.

The compounds of the present invention may be employed alone or incombination with other suitable therapeutic agents useful in thetreatment of the dysfunction of cellular membrane polarization andconductance, e.g., sexual dysfunction such as cyclic guaminemonophosphate, phosphodiaterase (cGMP PDE) inhibitors and particularlycGMP PDE V inhibitors such as sildenafil. Exemplary of the therapeuticagents are PDE V inhibitors selected from imidazo-quinazolines (see WO98/08848), carbazoles (see WO 97/03675, WO 97/03985 and WO 95/19978),imidazopurinones (see WO 97/19947), benzimidazoles (see WO 97/24334),pyrazoloquinolines (see U.S. Pat. No. 5,488,055), anthranilic acidderivatives (see WO 95/18097), fused heterocycles (see WO 98/07430) andthienopyrimidines (see DE 19632423). Alosetron hydrochloride can becombined with the compounds of the present invention to treat irritablebowel syndrome (see, e.g., U.S. Pat. Nos. 5,360,800 and 6,284,770).

The amount of compound actually administered will be determined by aphysician using sound medical judgement.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following examples are given by way of illustration and are not tobe construed as limiting the scope of the claims which follow.

In the following examples, all temperatures are given in degreesCentigrade. Melting points were recorded on a Gallenkamp capillarymelting point apparatus are uncorrected. Proton magnetic resonance (¹HNMR) spectra were recorded on a Bruker AC 300 or 500 megaHertz (“MHz”)spectrometer. All spectra were determined in the solvents indicated andchemical shifts are reported in δ units downfield from the internalstandard tetramethylsilane (TMS) and interproton coupling constants arereported in Hertz (Hz). Splitting patterns are designated as follows: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broadpeak; dd, doublet of doublet; bd, broad doublet; dt, doublet of triplet;bs, broad singlet; dq, doublet of quartet. Infrared (IR) spectra usingpotassium bromide (KBr) were determined on a Perkin Elmer 781spectrometer from 4000 cm⁻¹ to 400 cm⁻¹, calibrated to 1601 cm⁻¹absorption of a polystyrene film and reported in reciprocal centimeters(cm⁻¹). Low resolution mass spectra (MS) and the apparent molecularweight (MH⁺) or (M-H)— was determined on a Finnigan TSQ 7000. LC-MSanalysis were carried out on a Shimadzu instrument using one of thefollowing methods (1) YMC ODS C18 column (4.6×33 mm) employing a 4 minlinear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B(2) YMC ODS C18 column (4.6×30 mm) employing a 2 min linear gradient of0% to 100% solvent B in A and a 1 min hold at 100% B (3) YMC ODS C18column (3.0×50 mm) employing a 2 min linear gradient of 0% to 100%solvent B in A and a 1 min hold at 100% B (4) YMC ODS C18 column (3.0×50mm) employing a 4 min linear gradient of 0% to 100% solvent B in A and a1 min hold at 100% B. In all cases solvent A: 10% methanol, 90% water,0.1% TFA; and solvent B: 90% methanol, 10% water, 0.1% TFA with UVdetector set at 220 nm. The element analyses are reported as percent byweight. Unless otherwise indicated in the Specific Embodiments, R² andR⁴ are H in the descriptive title of the Examples.

Intermediates of Formula (V) Intermediate 1

2-Bromo-N-[2-(5-chloro-2-methoxy-benzoyl)-4-trifluoromethyl-phenyl]acetamide.To a solution of(2-Amino-5-trifluoromethyl-phenyl)-(5-chloro-2-methoxy-phenyl)-methanone(VI)(14.13 g, 42.9 mmol, 1 eq) in Dichloromethane (120 mL) at 0° C. wasadded pyridine (4.65 mL, 57.5 mmol, 1.34 eq), then Bromoacetyl bromide(4.98 mL, 57.2 mmol, 1.33 eq). After 3 h, the reaction was quenched withSodium bicarbonate (aq) and extracted three times into Dichloromethane.The combined organic layers were dried over Magnesium sulfate, filteredand concentrated in vacuo. The product was used without furtherpurification. ¹H NMR (300 MHz, CDCl3) δ 12.18 (s, 1H), 8.88 (d, J=8.9Hz, 1H), 7.82 (dd, J=1.9, 8.9 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.51 (dd,J=2.6, 8.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 4.08(s, 2H), 3.70 (s, 3H).

Intermediates of Formula (IV) Intermediate 2

4-(5-Chloro-2-methoxy-phenyl)-3-(4-methoxy-benzylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one.To a solution of p-methoxybenzylmercaptan (342 mg, 2.2 mmol, 4 eq) inTHF (4 mL) at 0° was added Sodium hydride (100 mg, 60% dispersion inmineral oil, 2.5 mmol, 4.5 eq). After 15 min, a solution of V (250 mg,555 μmol, 1 eq) in THF (2 mL) was added to the slurry dropwise. Thereaction was allowed to stir for 5 min at 0° before being allowed toreach RT over the course of 1 h. The reaction was quenched with 1M HCl,and extracted three times with Dichloromethane. The organic extractswere dried over Magnesium sulfate, and concentrated in vacuo.Chromatography (3/1, 1/1 Hexanes/EtOAc) provided pure IVa (273 mg, 97%).¹H NMR (300 MHz, CDCl₃) δ 13.21 (s, 1H), 7.72 (m, 2H), 7.43 (dd, J=2.6,8.8 Hz, 1H), 7.22 (s, 1H), 7.05–6.94 (m, 3H), 6.78 (d, J=8.6 Hz, 2H),6.34 (d, J=2.6 Hz, 1H), 4.61 (d, J=13.1 Hz, 1H), 3.97 (d, J=13.1 Hz,1H), 3.77 (s, 3H), 3.68 (s, 3H); LCMS (M+H) 506, RT=4.163 (Method 4).

Intermediate 3

3-tert-Butylsulfanyl-4-(5-chloro-2-methoxy-phenyl)-6-trifluoromethyl-1-H-quinolin-2-one.To a solution of 2-methyl-2-propanethiol (11.6 g, 129 mmol, 3 eq) in THF(300 mL) at 0° C. was added Sodium hydride (5.15 g, 60% dispersion inmineral oil, 129 mmol, 3 eq). After stirring for 20 min, solid V (42.9mmol) was added. The slurry was allowed to stir overnight. The reactionwas refluxed for 1 h, then cooled back to RT prior to quenching with 1MHCl. The product was extracted three times to EtOAc, dried overMagnesium sulfate, and concentrated in vacuo. Silica gel chromatography(50% EtOAc/Hex; EtOAc; 10% MeOH/EtOAc; 20% MeOH/EtOAc; 25% MeOH/acetone)provided pure IVb, 15.0 g, 82%.

Intermediates of Formula (III) Intermediate 4

4-(5-Chloro-2-methoxy-phenyl)-3-mercapto-6-trifluoromethyl-1H-quinolin-2-one.A solution of IVa (100. mg, 198 μmol) in TFA (1 mL) was refluxed for 45min. The excess TFA was removed in vacuo, and the residue was treatedwith dilute NaOH. The product was extracted three times to EtOAc, driedover Magnesium sulfate, and concentrated in vacuo. Chromatography (3:1,1:1 Hexane: EtOAc) provided pure IIIa (65.8 mg, 86%). ¹H NMR (300 MHz,CDCl₃) δ 12.67 (s, 1H), 7.69–7.56 (m, 2H), 7.52 (dd, J=2.6, 8.9 Hz, 1H),7.29–7.23 (m, 2H), 7.09 (d, J=8.9 Hz, 1H), 3.76 (s, 3H); LCMS (M+H) 386,RT=3.367 (Method 1).

Intermediate 5

4-(5-Chloro-2-hydroxy-phenyl)-3-mercapto-6-trifluoromethyl-1H-quinolin-2-one.To a solution of IVb (6.977 g, 16.3 mmol, 1 eq) in Dichloromethane (56mL) at −78° C. was added a 1 M solution of Boron tribromide inDichloromethane (25 mL, 25 mmol, 1.5 eq). After the addition wascomplete, the reaction was brought to RT, and stirred for an additional2 h. The reaction was brought back to −78° C., and quenched with Sodiumbicarbonate (sat'd). The mixture was extracted into Dichloromethane,dried over Magnesium sulfate, and dried in vacuo. The crude material wasrecrystalized from EtOAc/hexane to provide a yellow powder.

Intermediates of Formula (II) Intermediate 6

4-(5-Chloro-2-hydroxy-phenyl)-3-(4-methoxy-2-oxo-butylsulfanyl)-6-trifluoromethyl-]H-quinolin-2-one.To a solution of III (3.4 g, 9.2 mmol, 1 eq) in EtOH (100 mL) was addedPotassium carbonate (3.4 g, 25 mmol). After 15 min, a solution of1-Bromo-4-methoxy-butan-2-one (1.79 g, 9.9 mmol, 1.07 eq) in EtOH (9 mL)was added. After 20 min, LC/MS showed conversion to the product. Thereaction was filtered over glass wool and concentrated in vacuo. Thecrude product was purified by silica gel chromatography. Finalpurification was achieved by recrystallization from EtOAc/Hexane toprovide pure IIb (2.53 g, 59%). ¹H NMR (300 MHz, CD3SOCD3) δ 12.46 (s,1H), 9.96 (s, 1H), 7.83 (dd, J=1.7, 8.7 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H),7.39 (dd, J=2.7, 8.7 Hz, 1H), 7.14 (m, 2H), 7.02 (d, J=8.7 Hz, 1H), 4.00(d, J=15.1 Hz, 1H), 3.84 (d, J=15.1 Hz, 1H), 3.46 (t, J=6.4 Hz, 2H),3.16 (s, 3H), 2.67 (t, J=6.4 Hz, 2H); LCMS (M+H) 440, RT=1.743 (Method3).

Intermediate 7

3-(5-Chloro-2-oxo-pentylsulfanyl)-4-(5-chloro-2-hydroxy-phenyl)-6-trifluoromethyl-1H-quinolin-2-one.To a solution of III (5.87 g, 15.8 mmol, 1 eq) in EtOH (200 mL) wasadded Potassium carbonate (6.54 g, 47.4 mmol). After 15 min, a solutionof 1,5-Dichloropentan-2-one (3.47 g, 17.4 mmol, 1.10 eq) in EtOH (50 mL)was added. After 2 hr, LC/MS showed conversion to the product. Thereaction was filtered and concentrated in vacuo. The crude product waspurified by trituration with Chloroform to provide pure IIb (7.3 g,87%). ¹H NMR (300 MHz, CD₃OD) δ 7.76 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.36 (dd, J=2.6, 8.8 Hz, 1H), 7.30 (s, 1H), 7.06 (d, J=2.6 Hz,1H), 6.98 (d, J=8.8 Hz, 1H), 3.88 (d, J=14.3 Hz, 1H), 3.72 (d, J=14.3Hz, 1H), 3.39 (t, J=6.8 Hz, 2H), 2.67 (t, J=7.1 Hz, 2H), 2.10–1.90 (m,2H); LCMS (M+H) 490, RT=1.830 (Method 3).

Method for Preparing Examples 1–4, and 6–37

General procedure for the preparation of compounds Ia: To a solution ofIa (50.0 mg, 106 μmol, 1 eq) in THF (2 mL) was added a solution of theamine (498 μmol, 4.7 eq) in EtOH (498 μL). Solid Potassium carbonate wasadded, and the reaction allowed to stir overnight. The reaction wasfiltered, concentrated in vacuo, and purified by reverse phase HPLC toprovide the pure product Ia as a TFA salt. Examples 1–4 below andExamples 6–37 in Table 1 and 2 were prepared by this method.

Example 1

4-(5-Chloro-2-hydroxy-phenyl)-3-(4-morpholin-4-yl-2-oxo-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one.¹H NMR (300 MHz, CD₃OD) δ 7.81 (dd, J=1.9, 8.7 Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 7.39 (dd, J=2.6, 8.8 Hz, 1H), 7.33 (br s, 1H), 7.14 (d, J=2.6Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.09–4.05 (m, 2H), 3.92–3.78 (m, 2H),3.73 (d, J=14.6 Hz, 1H), 3.63–3.51 (m, 3H), 3.49–3.40 (m, 2H), 3.25–3.07(m, 4H); LCMS (M+H) 527, RT=2.697 (Method 4).

Example 2

4-(5-Chloro-2-hydroxy-phenyl)-3-(2-oxo-4-pyrrolidin-1-yl-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one.¹H NMR (300 MHz, CD₃OD) δ 7.79 (dd, J=1.8, 8.7 Hz, 1H), 7.54 (d, J=8.7Hz, 1H), 7.38 (dd, J=2.6, 8.7 Hz, 1H), 7.32 (br s, 1H), 7.13 (d, J=2.6Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 3.98–3.63 (m, 4H), 3.45 (t, J=6.4 Hz,2H), 3.17 (t, J=6.4 Hz, 2H), 3.11–3.09 (m, 2H), 2.16–2.03 (m, 4H); LCMS(M+H) 511, RT=1.583 (Method 3).

Example 3

4-(5-Chloro-2-hydroxy-phenyl)-3-[4-(4-methyl-piperazin-1-yl)-2-oxo-butylsulfanyl]-6-trifluoromethyl-1H-quinolin-2-one.¹H NMR (300 MHz, CD₃OD) δ 7.81 (dd, J=1.7, 8.7 Hz, 1H), 7.57 (d, J=8.6Hz, 1H), 7.39 (dd, J=2.6, 8.8 Hz, 1H), 7.33 (br s, 1H), 7.13 (d, J=2.6Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 3.74 (d, J=14.5 Hz, 1H), 3.62 (d,J=14.5 Hz, 1H), 3.59–3.49 (m, 8H), 3.36 (t, J=6.3 Hz, 2H), 3.17–3.13 (m,2H), 2.96 (s, 3H); LCMS (M+H) 540, RT=1.503 (Method 3).

Example 4

4-(5-Chloro-2-methoxy-phenyl)-3-(4-morpholin-4-yl-2-oxo-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one.¹H NMR (300 MHz, CD₃OD) δ 7.77 (dd, J=1.9, 8.8 Hz, 1H), 7.55–7.51 (m,2H), 7.22–7.16 (m, 3H), 4.12 (d, J=7.1 Hz, 1H), 4.07 (d, J=7.1 Hz, 1H),3.74 (s, 3H), 3.74–3.67 (m, 4H), 2.85–2.70 (m, 4H), 2.66–2.56 (m, 4H);LCMS (M+H) 541, RT=1.633 (Method 3).

Method for Preparing Examples 38–83

General Procedure for the preparation of Compounds Ib: To a solution ofIIb (50.0 mg, 102 μmol, 1 eq) in THF (500 μL) was added a solution ofthe amine (1.02 μmol, 10 eq) in THF (750 μL). The reaction was allowedto stir for 48 hrs. The reaction was concentrated in vacuo, and purifiedby reverse phase HPLC to provide the pure product Ib as a TFA salt.Examples 38–83 in Table 1 and 2 were prepared by this method.

Intermediates of Formula (VII) Intermediate 8

[4-(5-Chloro-2-hydroxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-quinolin-3-ylsulfanyl]-acetic acid methyl ester. To make the phenolic series(R═H), first follow the following procedure: To a solution of V (16.3mmol, 1 eq) in Dichloromethane (56 mL) at −78° C. was added a 1 Msolution of Boron tribromide in Dichloromethane (25 mL, 25 mmol, 1.5eq). After the addition was complete, the reaction was brought to RT,and stirred for an additional 2 h. The reaction was brought back to −78°C., and quenched with Sodium bicarbonate (sat'd). The mixture wasextracted into Dichloromethane, dried over Magnesium sulfate, and driedin vacuo. To a stirred suspension of Sodium hydride (838 mg of a 60%dispersion in mineral oil, 20.9 mmol, 2 eq) in THF (150 mL) was addedmethyl thioglycolate (1.86 mL, 20.9 mmol, 2 eq) and allowed to stir atRT for 10 minutes. A solution of V (4.57 g, 10.5 mmol, 1 eq) in THF wasthen added, and the mixture stirred for 3 h. More Sodium hydride (418mg, 10.5 mmol, 1 eq) was added, and stirring continued overnight. Thereaction was carefully quenched with 1N HCl, and extracted three timesinto EtOAc. The combined organic layers were dried over Magnesiumsulfate, and concentrated in vacuo.

Intermediates of Formula (VIII) Intermediate 9

[4-(5-Chloro-2-hydroxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-quinolin-3-ylsulfanyl]-acetic acid. The crude compound VII was taken up in THF towhich 10N NaOH was added (1:1 by volume). After stirring overnight, thereaction was quenched with 4N HCl, and extracted three times to EtOAc.The combined organic layers were dried over Magnesium sulfate, andconcentrated in vacuo. The product was taken up in warm 95%Dichloromethane/MeOH. After cooling, the white solid was filtered offand dried to give pure VIII.

Method for Preparing Examples 5, and 84–108

General Procedure for the preparation of Compounds Ic. To a solution ofVIII (200. mg, 465 μmol, 1 eq) in THF (4 mL) and 1,2-dichloroethane (4mL) was added EDC (180 mg, 939 mmol, 2 eq), and then the amine (939mmol, 2 eq). After 4 hours, the reaction was concentrated in vacuo, andpurified by reverse phase HPLC. Concentration of the appropriatefractions gave pure Ic. Example 5 below and Examples 84–108 in Table 1and 2 were prepared by this method.

Example 5

4-(5-Chloro-2-hydroxy-phenyl)-3-[2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethylsulfanyl]-6-trifluoromethyl-1H-quinolin-2-one.¹H NMR (300 MHz, CD₃OD) δ 7.77 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.6 Hz,1H), 7.38 (dd, J=2.5, 8.7 Hz, 1H), 7.30 (br s, 1H), 7.14–6.97 (m, 2H),4.66–4.52 (m, 1H), 4.24–3.92 (m, 2H), 3.88–3.69 (m, 1H), 3.54–3.36 (m,1H), 3.16–2.57 (m, 8H), 2.18–2.02 (m, 2H), 1.92–1.51 (m, 2H); LCMS (M+H)539, RT=1.417 (Method 1).

The following examples, found to be modulators of the Maxi-K channel,were also made by the above methods.

Retention HPLC Example Structure time (min) Method** MS 6

1.777 2 527 7

1.597 3 525 8

1.583 3 543 9

1.96 3 625 10

1.60 3 527 11

1.59 3 554 12

1.71 3 553 13

1.68 3 553 14

1.74 3 651 15

1.66 3 597 16

1.71 3 579 17

1.54 3 554 18

1.60 3 551 19

1.64 3 541 20

1.61 3 539 21

1.48 3 570 22

1.69 3 567 23

1.58 3 569 24

1.54 3 555 25

1.61 3 527 26

1.69 3 575 27

1.53 3 568 28

1.61 3 539 29

1.62 3 539 30

1.53 3 541 31

1.53 3 568 32

1.70 3 541 33

1.70 3 554 34

1.62 3 597 35

1.54 3 556 36

1.59 3 555 37

1.50 3 608 38

1.523 3 540 39

1.563 3 540 40

1.557 3 558 41

1.463 3 555 42

1.55 3 541 43

1.63 3 567 44

1.62 3 567 45

1.75 3 665 46

1.61 3 611 47

1.67 3 593 48

1.52 3 555 49

1.74 3 629 50

1.50 3 568 51

1.56 3 565 52

1.60 3 555 53

1.44 3 556 54

1.63 3 605 55

1.56 3 553 56

1.45 3 584 57

1.64 3 581 58

1.53 3 583 59

1.51 3 569 60

1.59 3 541 61

1.66 3 589 62

1.69 3 617 63

1.49 3 582 64

1.53 3 525 65

1.58 3 553 66

1.59 3 553 67

1.50 3 555 68

1.44 3 568 69

1.58 3 611 70

1.43 3 570 71

1.53 3 569 72

1.46 3 622 73

1.50 3 538 74

1.65 3 593 75

1.71 3 651 76

1.50 3 590 77

1.44 3 584 78

1.56 3 551 79

1.54 3 634 80

1.63 3 656 81

1.60 3 649 82

1.44 3 628 83

1.73 3 639 84

2.667 1 512 85

3.047 1 499 86

3.167 1 483 87

3.293 1 515 88

3.283 1 485 89

2.917 1 545 90

2.790 1 542 91

2.793 1 556 92

2.757 1 520 93

1.973 2 539 94

1.703 2 526 95

1.680 2 534 96

1.54 3 540 97

1.53 3 526 98

1.44 3 586 99

1.49 3 548 100

1.46 3 526 101

1.82 3 525 102

1.69 3 570 103

1.43 3 542 104

1.72 3 569 105

1.53 3 540 106

1.55 3 487 107

1.51 3 584 108

1.75 3 583 **(1) YMC ODS C18 column (4.6 × 33 mm) employing a 4 minlinear gradient of 0% to 100% solvent B in A and a 1 min hold at 100% B(2) YMC ODS C18 column (4.6 × 30 mm) employing a 2 min linear gradientof 0% to 100% solvent B in A and a 1 min hold at 100% B (3) YMC ODS C18column (3.0 × 50 mm) employing a 2 min linear gradient of 0% to 100%solvent B in A and a 1 min hold at 100% B (4) YMC ODS C18 column (3.0 ×50 mm) employing a 4 min linear gradient of 0% to 100% solvent B in Aand a 1 min hold at 100% B. In all cases solvent A: 10% methanol, 90%water, 0.1% TFA; and solvent B: 90% methanol, 10% water, 0.1% TFA withUV detector set at 220 nm.

1. A compound of formula (I)

wherein: R and R¹ are independently hydrogen or methyl; R², R³, and R⁴are independently hydrogen, halogen, cyano, nitro, or trifluoromethyl,provided R², R³, and R⁴ are not all hydrogen; R⁵ is bromo, chloro, ornitro; R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl,C₃₋₇ cycloalkyl, —CH₂C₃₋₇ cycloalkyl, —(CH₂)₁₋₃OH, —(CH₂)₂₋₃NR⁸R⁹,—(CH₂)₁₋₃CN, or —(CH₂)₁₋₃Ar, where Ar is selected from the groupconsisting of phenyl, naphthyl, furanyl, thienyl, and pyridyl, and Ar isunsubstituted or substituted with 1–2 methoxy substituents; or NR⁶R⁷taken together form

or NR⁶R⁷ taken together are selected from the group consisting of

R⁸ and R⁹ are independently hydrogen or C₁₋₆alkyl; R¹⁰ is a bond, O, S,NR¹¹, or CHR¹²; R¹¹ is hydrogen, C₁₋₆ alkyl, CHO, C(O)Me, —(CH₂)₂₋₃OH,—CH₂CH₂OCH₂CH₂OH, —C(O)furanyl, or —CH₂CH═CHPh; R¹² is hydrogen,hydroxy, C₁₋₆ alkyl, —CH₂Ph, —C(O)OR⁸, —(CH₂)NR⁸R⁹, or 1-piperidinyl; mis 0, 1, 2, or 3; or a nontoxic pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 where R is hydrogen.
 3. A compound ofclaim 1 where R¹ is hydrogen.
 4. A compound of claim 1 where R² ishydrogen, R³ is trifluoromethyl, and R⁴ is hydrogen.
 5. A compound ofclaim 1 where R⁵ is chloro.
 6. A compound of claim 1 where m is
 3. 7. Acompound of claim 1 selected from the group consisting of (1)4-(5-Chloro-2-hydroxy-phenyl)-3-(4-morpholin-4-yl-2-oxo-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one;(2)4-(5-Chloro-2-hydroxy-phenyl)-3-(2-oxo-4-pyrrolidin-1-yl-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one;(3)4-(5-Chloro-2-hydroxy-phenyl)-3-[4-(4-methyl-piperazin-1-yl)-2-oxo-butylsulfanyl]-6-trifluoromethyl-1H-quinolin-2-one;(4)4-(5-Chloro-2-methoxy-phenyl)-3-(4-morpholin-4-yl-2-oxo-butylsulfanyl)-6-trifluoromethyl-1H-quinolin-2-one;(5)4-(5-Chloro-2-hydroxy-phenyl)-3-[2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethylsulfanyl]-6-trifluoromethyl-1H-quinolin-2-one;(6)4-(5-Chloro-2-methoxyphenyl)-3-[[4-(diethylamino)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(7)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-4-(1-piperidinyl)butyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(8)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-4-(4-thiomorpholinyl)butyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(9)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(dihexylamino)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(10)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(3-hydroxy-1-pyrrolidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(11)1-[4-[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-(2S)-2-pyrrolidinecarboxamide;(12)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(cyclohexylmethylamino)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(13)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[(cyclopropylmethyl)propylamino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(14)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-4-[(2phenylethyl)(phenylmethyl)amino]butyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(15)1-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-3-piperidinecarboxylic acid, ethylester; (16)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(octahydro-1(2H)-quinolinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(17)4-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-1-piperazinecarboxaldehyde; (18)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[(2-furanylmethyl)methylamino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(19)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(dipropylamino)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(20)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(2-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(21)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(22)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(5-ethyl-2-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(23)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[2-(2-hydroxyethyl)-1-piperidinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(24)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[3-(hydroxymethyl)-1-piperidinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(25)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[methyl(2-methylpropyl)amino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(26)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[methyl(2-phenylethyl)amino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(27)1-Acetyl-4-[4-[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]piperazine;(28)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(3-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(29)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(4-methyl-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(30)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-(4-hydroxy-1-piperidinyl)-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(31)1-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-3-piperidinecarboxamide;(32)3-[[4-(Butylethylamino)-2-oxobutyl]thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;(33)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[methyl(1-methyl-3-pyrrolidinyl)amino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(34)1-[4-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-3-oxobutyl]-4-piperidinecarboxylicacid, ethyl ester; (35)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[[3-(dimethylamino)propyl]methylamino]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;(36)4-(5-Chloro-2-hydroxyphenyl)-3-[[4-[2-(hydroxymethyl)-1-piperidinyl]-2-oxobutyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(37)3-[(4-[1,4′-Bipiperidin]-1′-yl-2-oxobutyl)thio]-4-(5-chloro-2-hydroxyphenyl)6-(trifluoromethyl)-2(1H)-quinolinone;(38)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-morpholinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(39)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-(1-piperidinyl)pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(40)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-(4-thiomorpholinyl)pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(41)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-methyl-1-piperazinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(42)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(3-hydroxy-1-pyrrolidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(43)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(cyclohexylmethylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(44)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[(cyclopropylmethyl)propylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(45)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-[(2-phenylethyl)(phenylmethyl)amino]pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(46)1-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]-3-piperidinecarboxylic acid, ethylester; (47)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(octahydro-1(2H)-quinolinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(48)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[2-(hydroxymethyl)-1-pyrrolidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(49)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-[4-(phenylmethyl)-1-piperidinyl]pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(50)4-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]-1-piperazinecarboxaldehyde; (51)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[(2-furanylmethyl)methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(52)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(dipropylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(53)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[2-(dimethylamino)ethyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(54)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[(2-hydroxy-2-phenylethyl)methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(55)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(2-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(56)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[4-(2-hydroxyethyl)-1-piperazinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(57)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(5-ethyl-2-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(58)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[2-(2-hydroxyethyl)-1-piperidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(59)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[3-(hydroxymethyl)-1-piperidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(60)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl(2-methylpropyl)amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(61)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl(2-phenylethyl)amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(62)3-[[5-[Butyl(phenylmethyl)amino]-2-oxopentyl]thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;(63)1-Acetyl-4-[5-[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]piperazine;(64) 4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-(1-pyrrolidinyl)pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone; (65)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(3-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(66)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-methyl-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(67)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(4-hydroxy-1-piperidinyl)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(68)4-(5-chloro-2-hydroxyphenyl)-3-[[5-[methyl(1-methyl-3-pyrrolidinyl)amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(69)1-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]-4-piperidinecarboxylicacid, ethyl ester; (70)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[3-(dimethylamino)propyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)quinolinone;(71)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[2-(hydroxymethyl)-1-piperidinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(72)3-[(5-[1,4′-Bipiperidin]-1′-yl-2-oxopentyl)thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;(73)3-[[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]methylamino]propanenitrile;(74)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(cyclohexyl-2-propenylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(75)3-[[5-[bis(Phenylmethyl)amino]-2-oxopentyl]thio]-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-quinolinone;(76) 4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl [2-(2-pyridinyl)ethyl]amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone; (77)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[2-(diethylamino)ethyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(78)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-(di-2-propenylamino)-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(79)1-[5-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-4-oxopentyl]-4-(2-furanylcarbonyl)piperazine;(80)4-(5-Chloro-2-hydroxyphenyl)-3-[[2-oxo-5-[4-[(2E)-3-phenyl-2-propenyl]-1-piperazinyl]pentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(81)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(82)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(83)4-(5-Chloro-2-hydroxyphenyl)-3-[[5-[methyl[1-naphthalenyl)ethyl]amino]-2-oxopentyl]thio]-6-(trifluoromethyl)-2(1H)-quinolinone;(84)1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-methylpiperazine;(85)4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]morpholine;(86)1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]pyrrolidine;(87)4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]thiomorpholine;(88)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N,N-diethylacetamide;(89)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N,N-bis(2-hydroxypropyl)acetamide;(90)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(diethylamino)ethyl]-N-methylacetamide;(91)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[3-(4-morpholinyl)propyl]acetamide;(92)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-(3-pyridinylmethyl)acetamide;(93)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(2-thienyl)ethyl]acetamide;(94)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(1-pyrrolidinyl)ethyl]acetamide;(95)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-[2-(4-pyridinyl)ethyl]acetamide;(96)1-Acetyl-4-[[[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]piperazine;(97)4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazinecarboxaldehyde;(98)2-[2-[4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazinyl]ethoxy]ethanol;(99)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-ethyl-N-(4-pyridinylmethyl)acetamide;(100)1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl] hexahydro-4-methyl-1H-1,4-diazepine; (101)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-(cyclopropylmethyl)-N-propylacetamide;(102)4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazinecarboxylicacid, ethyl ester; (103)4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazineethanol;(104)1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-piperidinecarboxylicacid, ethyl ester; (105)1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-piperidinecarboxamide;(106)2-[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]-N-(2-hydroxyethyl)-N-methylacetamide;(107)4-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-1-piperazineaceticacid, ethyl ester; and (108)1-[[[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolinyl]thio]acetyl]-4-oxo-3-piperidinecarboxylicacid, ethyl ester.
 8. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.